pubs.acs.org/joc
reaction could provide general access to aryl amines as a
Synthesis of Primary Aryl Amines Through a
Copper-Assisted Aromatic Substitution Reaction
with Sodium Azide
complement to existing procedures for aromatic amination
most commonly with copper or palladium catalysts and
4
either masked nitrogen sources or ammonia directly.
5
The previous literature on the use of sodium azide in
aromatic substitution reactions consists of a confusing var-
iety of results with respect to whether the products are aryl
azides or amines. Ma reported the reaction of a variety of
electron-rich or electron-poor aryl iodides, aryl bromides,
John T. Markiewicz, Olaf Wiest, and Paul Helquist*
Department of Chemistry and Biochemistry,
University of Notre Dame, 251 Nieuwland Science Hall,
Notre Dame, Indiana 46556
and alkenyl iodides with excess NaN and catalytic quanti-
3
2a
ties of CuI and proline to form the corresponding azides.
Similar results were obtained by Liang using diamine ligands
2
b
Received May 21, 2010
in place of proline and by Ackermann for the in situ gene-
ration of aryl azides as participants in a cascade reaction
6
sequence involving “click” [3þ2] cycloadditions. Similarly,
Molander and Ham described the use of stoichiometric
NaN , Cs CO , catalytic CuBr, and N,N -dimethylethylene-
0
3
2
3
diamine (DMEDA) in a general procedure for conversion of
potassium haloaryltrifluoroborates into the corresponding
azidoaryltrifluoroborates, but in a small number of cases, the
corresponding amines were instead obtained without a clear
7
pattern of dependence on substituent effects. Fu and Qiao
found a pronounced substituent effect when employing
excess NaN , Cs CO , or K CO , and catalytic CuI whereby
A method is presented by which aryl halides and azides
are converted to the corresponding primary aryl amines
with copper(I) and sodium azide.
3
2
3
2
3
aryl-halides bearing o-carboxyl, -carboxamide, or -amino-
carbonyl groups underwent conversion to the corresponding
aryl amines, but other substitution patterns led either to an
azide or to lack of reactivity of the halide. Of relevance to
later discussion (vide infra), nitro substituents survived un-
changed under the Fu and Qiao amination conditions with-
Metal-promoted transformations of aryl halides and pseudo-
halides to various heteroatomic functional groups is an ever-
expanding class of reactions in synthetic chemistry. These
reactions provide new routes to many compounds of medici-
nal and industrial importance. Among these reactions, seve-
ral methods for the formation of carbon-nitrogen bonds
8
out concomitant reduction. Thatcher reported a single
isolated example of the conversion of a fairly complex aryl
bromide into an aryl amine using excess NaN and stoichio-
3
9
metric NaOH, CuI, and proline. Sajiki recently published a
1
have become especially prominent.
method employing trimethylsilyl azide and CuF , which has
2
In the course of a medicinal chemistry effort, we had need
for such a reaction to convert a complex aromatic bromide to
the corresponding azide to serve as an affinity probe. In an
attempt to employ previously reported conditions to accom-
plish this transformation, we unexpectedly obtained an
3
amine instead of the azide as the product in high yield (eq 1).
broad scope for the synthesis of aryl amines without forma-
1
0
tion of azides. Finally, there have also been reports of
reactions of NaN without a catalyst to convert aryl halides
3
1
1
12
2
into amines and of nitroaromatics into aryl azides. With
the backdrop of this bewildering array of reports, we sought
˚
4) (a) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald,
(
S. L. Tetrahedron Lett. 1997, 38, 6367. (b) Lee, D.-Y.; Hartwig, J. F. Org.
Lett. 2005, 7, 1169.
(5) (a) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028.
b) Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 10354. (c) Vo,
(
G. D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 11049. (d) Jiang, L; Lu, X.;
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Q.; Dinga, K. Adv. Synth. Catal. 2009, 351, 1722. (f) Xia, N.; Taillefer, M. A.
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diazotization reaction of the amine. The formation of the
amine as the initial product led us to consider whether this
(6) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org.
Lett. 2008, 10, 3081–3084.
(7) Cho, Y. A.; Kim, D.-S.; Ahn, H. R.; Canturk, B.; Molander, G. A.;
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(8) Zhao, H.; Fu, H.; Qiao, R. J. Org. Chem. 2010, 75, 3311.
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(10) Monguchi, Y.; Maejima, T.; Mori, S.; Maegawa, T.; Sajiki, H.
Chem.;Eur. J. DOI: 10.1002/chem.200903511. Published Online: May 18,
2010.
(
1) (a) Kienle, M.; Dubbaka, R. S.; Brade, K.; Knochel, P. Eur. J. Org.
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3) Cosner, C. C.; Markiewicz, J. T.; Bourbon, P.; Mariani, C. J.; Wiest,
4
(
(
(
O.; Rujoi, M.; Rosenbaum, A. I.; Huang, A. Y.; Maxfield, F. R.; Helquist, P.
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DOI: 10.1021/jo101002p
r 2010 American Chemical Society
Published on Web 06/22/2010
J. Org. Chem. 2010, 75, 4887–4890 4887